Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGT1A7 gene.

BACKGROUND & AIMS Hepatocellular carcinoma is associated with risk factors including hepatitis C, hepatitis B, cirrhosis, genetic liver diseases, and environmental carcinogens. Uridine 5'-diphosphate-glucuronosyltransferases are a superfamily of detoxifying enzymes capable of tobacco-borne carcinogen detoxification and cellular protection. This study examines the association of UGT1A7 and UGT1A9 gene polymorphisms with hepatocellular carcinoma. METHODS Genomic DNA from the blood of 59 patients with hepatocellular carcinoma and 70 control subjects without evidence of cancer was analyzed by UGT1A7- and UGT1A9-specific PCR, sequencing analysis, and temperature gradient gel electrophoresis. RESULTS Three UGT1A7 missense mutations were detected defining the UGT1A7*2, UGT1A7*3, and UGT1A7*4 alleles. Wild-type UGT1A7 alleles were present in 41.4% of controls but only in 6.8% of cancer patients (P < 0.001; odds ratio [OR], 9.73; 95% confidence interval [CI], 3.17-29.83). UGT1A7 polymorphisms were present in 93.2% of hepatocellular cancer patients, 74.5% carried the UGT1A7*3 allele (P < 0.001; OR, 10.76; 95% CI, 4.75-24.38), which combines the W208R, N129K, and R131K mutations and encodes a protein with low carcinogen detoxification activity. No UGT1A9 polymorphisms were detected. CONCLUSIONS The significant association of hepatocellular carcinoma with the UGT1A7*3 allele encoding a low detoxification activity protein is identified and implicates UGT1A7 as a risk gene of hepatocarcinogenesis in addition to a role as potential marker for cancer risk assessment in chronic liver disease.

[1]  R. Tukey,et al.  Glucuronide and glucoside conjugation of mycophenolic acid by human liver, kidney and intestinal microsomes , 2001, British journal of pharmacology.

[2]  R. Tukey,et al.  Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract. , 2001, Molecular pharmacology.

[3]  H. El‐Serag,et al.  Risk factors for the rising rates of primary liver cancer in the United States. , 2000, Archives of internal medicine.

[4]  M. Manns,et al.  Polymorphic Gene Regulation and Interindividual Variation of UDP-glucuronosyltransferase Activity in Human Small Intestine* , 2000, The Journal of Biological Chemistry.

[5]  C. Guillemette,et al.  Structural heterogeneity at the UDP-glucuronosyltransferase 1 locus: functional consequences of three novel missense mutations in the human UGT1A7 gene. , 2000, Pharmacogenetics.

[6]  M. Barton,et al.  Hepatitis B viral transactivator HBx alleviates p53-mediated repression of alpha-fetoprotein gene expression. , 2000, The Journal of biological chemistry.

[7]  M. Manns,et al.  Jaundice, genes and promoters. , 2000, Journal of hepatology.

[8]  A. Ohnishi,et al.  Genotype analysis of the CYP2C19 gene in HCV-seropositive patients with cirrhosis and hepatocellular carcinoma. , 2000, Life sciences.

[9]  R. Santella,et al.  Effects of carcinogen‐induced transcription factors on the activation of hepatitis B virus expression in human hepatoblastoma HepG2 cells and its implication on hepatocellular carcinomas , 2000, Hepatology.

[10]  M. Manns,et al.  Hepatocellular carcinoma in Germany: a retrospective epidemiological study from a low-endemic area. , 2000, Liver.

[11]  W. Caselmann,et al.  Carcinogenesis of primary liver malignancies , 2000, Langenbeck's Archives of Surgery.

[12]  A. Tannapfel,et al.  p53 mutation pattern in hepatocellular carcinoma in workers exposed to vinyl chloride , 2000, Cancer.

[13]  H. Adami,et al.  Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma , 2000, International journal of cancer.

[14]  H. Bartsch,et al.  ras gene mutations in vinyl chloride‐induced liver tumours are carcinogen‐specific but vary with cell type and species , 2000, International journal of cancer.

[15]  L. Seeff,et al.  Natural history of hepatitis C , 1997, Hepatology.

[16]  J. Groopman,et al.  Aflatoxin and liver cancer. , 1999, Bailliere's best practice & research. Clinical gastroenterology.

[17]  R. Tukey,et al.  Glucuronidation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4, 5-b]pyridine by human microsomal UDP-glucuronosyltransferases: identification of specific UGT1A family isoforms involved. , 1999, Carcinogenesis.

[18]  Y. Liaw,et al.  ©1999 Cancer Research Campaign Article no. bjoc.1998.0397 , 2022 .

[19]  C. J. Chen,et al.  Plasma carotenoids, glutathione S-transferase M1 and T1 genetic polymorphisms, and risk of hepatocellular carcinoma: independent and interactive effects. , 1999, American journal of epidemiology.

[20]  C. J. Chen,et al.  Ap53genetic polymorphism as a modulator of hepatocellular carcinoma risk in relation to chronic liver disease, familial tendency, and cigarette smoking in hepatitis B carriers , 1999, Hepatology.

[21]  M. Manns,et al.  Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus. , 1999, The Biochemical journal.

[22]  M. Manns,et al.  Polymorphic expression of the UDP-glucuronosyltransferase UGT1A gene locus in human gastric epithelium. , 1998, Molecular pharmacology.

[23]  M. Manns,et al.  Expression of the UDP-glucuronosyltransferase 1A Locus in Human Colon , 1998, The Journal of Biological Chemistry.

[24]  M. Manns,et al.  Differential expression of the UGT1A locus in human liver, biliary, and gastric tissue: identification of UGT1A7 and UGT1A10 transcripts in extrahepatic tissue. , 1997, Molecular pharmacology.

[25]  M. Manns,et al.  Differential down-regulation of the UDP-glucuronosyltransferase 1A locus is an early event in human liver and biliary cancer. , 1997, Cancer research.

[26]  J. Yoon,et al.  Lack of association of cytochrome P450 2E1 genetic polymorphisms with the risk of human hepatocellular carcinoma , 1997, International journal of cancer.

[27]  C. J. Chen,et al.  Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. , 1995, Gastroenterology.

[28]  H. Tillmann,et al.  Analysis of hepatitis C virus genome in patients with autoimmune hepatitis type 2. , 1994, Gastroenterology.

[29]  S. De Flora,et al.  Carcinogen metabolism in human lung tissues and the effect of tobacco smoking: results from a case--control multicenter study on lung cancer patients. , 1992, Environmental health perspectives.

[30]  R. Wooster,et al.  Cloning and stable expression of a new member of the human liver phenol/bilirubin: UDP-glucuronosyltransferase cDNA family. , 1991, The Biochemical journal.

[31]  R. Tukey,et al.  Human UDP-glucuronosyltransferases: metabolism, expression, and disease. , 2000, Annual review of pharmacology and toxicology.

[32]  M. Ozturk.  Genetic Aspects of Hepatocellular Carcinogenesis , 1999, Seminars in liver disease.

[33]  M. Manns,et al.  UDP-glucuronosyltransferase activity in human liver and colon. , 1999, Gastroenterology.

[34]  T. Lash,et al.  Active and passive cigarette smoking and the occurrence of breast cancer. , 1999, American journal of epidemiology.

[35]  M. Colombo,et al.  Natural history and pathogenesis of hepatitis C virus related hepatocellular carcinoma. , 1999, Journal of hepatology.

[36]  E. Wynder,et al.  Smoking and pancreatic cancer in men and women. , 1997, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[37]  C. Harris,et al.  p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. , 1994, Carcinogenesis.

[38]  P. Vineis.  Epidemiological models of carcinogenesis: the example of bladder cancer. , 1992, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.